34391-04-3
| Name | Salbutamol |
| CAS | 34391-04-3 |
| EINECS(EC#) | 242-424-0 |
| Molecular Formula | C13H21NO3 |
| MDL Number | MFCD00869868 |
| Molecular Weight | 239.31 |
| MOL File | 34391-04-3.mol |
Synonyms
(L)-ALBUTEROL
LEVALBUTEROL
LEVALBUTEROL HCL
R-SALBUTAMOL HCL
(-)-alpha(sup1)-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-1,3-benzenedime
1,3-benzenedimethanol,alpha(sup1)-(((1,1-dimethylethyl)amino)methyl)-4-hydrox
alpha’-diol,alpha(sup1)-((tert-butylamino)methyl)-4-hydroxy-m-xylene-alph
r-albuterol
Levalbutreol
2-(hydroxymethyl)-4-[1-hydroxy-2-(tert-butylamino)ethyl]phenol
LEVOSALBUTEROLHCL
1,3-Benzenedimethanol, a1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-, (a1R)-(9CI)
1,3-Benzenedimethanol, a1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-, (R)-
Levosalbutamol
m-Xylene-a,a'-diol, a1-[(tert-butylamino)methyl]-4-hydroxy-, (R)-(-)-(8CI)
2-(hydroxymethyl)-4-[(1R)-1-hydroxy-2-(tert-butylamino)ethyl]phenol
4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol
Salbutamol
(R)-1-(4-Hydroxy-3-hydroxymethylphenyl)-2-(1,1-dimethylethylamino)ethanol
(R)-1-(4-Hydroxy-3-hydroxymethylphenyl)-2-tert-butylaminoethanol
Chemical Properties
| Boiling point | 433.5±40.0 °C(Predicted) |
| density | 1.152±0.06 g/cm3(Predicted) |
| pka | 9.99±0.31(Predicted) |
| InChI | InChI=1/C13H21NO3/c1-13(2,3)14-7-12(17)9-4-5-11(16)10(6-9)8-15/h4-6,12,14-17H,7-8H2,1-3H3/t12-/s3 |
| InChIKey | NDAUXUAQIAJITI-PLAQIDKDNA-N |
| SMILES | C1(=CC=C(O)C(CO)=C1)[C@@H](O)CNC(C)(C)C |&1:9,r| |
| CAS DataBase Reference | 34391-04-3(CAS DataBase Reference) |
Safety Data
| Hazard Codes | Xn |
| Risk Statements |
R22:Harmful if swallowed.
|
| Safety Statements |
S36:Wear suitable protective clothing .
|
| HS Code | 2922509090 |
Hazard Information
Originator
Sepracor (US)
Uses
(R)-Salbutamol is used in composition and methods to reduce beta-agonist-mediated tachyphylaxis.
Uses
Salbutamol is the β2-agonist used most commonly for the prevention and
treatment of bronchospasm. I t is most commonly administered in its inhaled
form by metered-dose inhaler (1–2 puffs of 100μg each) or via nebuliser in
more severe cases of bronchospasm (2.5–5mg). In patients with lifethreatening
asthma it may be administered i.v. as both a bolus (250μg) and
infusion (3–20μgmin –1). Intravenous administration requires cardiac
monitoring as tachyarrhythmias may be significant. Salbutamol may also be
used in the management of hyperkalaemia, temporarily driving K+
intracellularly via stimulation of the Na+–K+ ATPase pump.
Definition
ChEBI:(R)-salbutamol is an albuterol.
Manufacturing Process
Preparation of 5-glyoxyloyl-salicylic acid methyl ester hydrate using aqueous
HBr
To a 3-neck flask immersed in an oil bath containing a solution of 40 g (0.206 mole) methyl 5-acetylsalicylate in 6 ml methylene chloride is charged with 82 ml of isopropanol. The solution is distilled to remove excess methylene chloride. When the internal temperature reaches 77°C, 126 ml (1.77 mole or 8.6 equivalents) of DMSO is added to the reaction mixture and the temperature of the mixture is increased to a temperature of 85° to 90°C. Then 33 ml (0.29 mole or 1.4 equivalents) of HBr (aqueous, 48%) is added to the mixture over a period of 20 minutes (exothermic), and the bath temperature is maintained at 95° to 100°C. As the addition of HBr nears completion distillation is initiated and dimethysulfide and isopropanol are distilled off. The mixture is stirred and the volume of the distillate monitored. After distillation of 82 ml of solvent, 20 ml of isopropanol is added slowly to maintain a steady rate of distillation. After the reaction completed asdetermined by high performance liquid chromatography (HPLC), the reaction mixture is quenched with 70 ml of 2.4 N H2SO4, the temperature of the reaction mixture is allowed to drop to 75°C and residual isopropanol is distilled off under vacuum. After a total of 165 ml distillate is collected, the title compound begins to precipitate. A mixture of 30 ml of acetonitrile and 70 ml of water is added slowly at 75°C with stirring. After 30 minutes of stirring, the reaction mixture is cooled to 15°C over a period of 90 minutes to complete the precipitation. The reaction mixture is filtered and the cake is washed with three 300 ml portions of water. The cake is dried in a draft oven at 50°C for 16 hours to give 39.5 g of the title compound (85% yield).
Preparation of albuterol from 5-glyoxyloyl-salicylic acid methyl ester
To a solution of 5-glyoxyloylsalicylic acid methyl ester hydrate (50 g, 0.221 mol) in ethylene glycol diethyl ether, 440 mL is added tertiary butylamine (16.2 g, 0.221 mol) at room temperature. The resulting light orange solution is stirred for 5 min until a clear solution is formed. The clear solution is then heated to reflux. Water and DME are distilled off azeotropically. After a total of 200 ml of distillate are collected, the solution is cooled to 25°C. The reaction mixture is slowly added to a solution containing 49 mL (0.49 mol) of 10.0 M borane-dimethyl sulfide in 220 mL of ethylene glycol diethyl ether (DME) at 70°C. The resulting reaction mixture is further refluxed for 2.5 hrs. After the reaction is completed as monitored by HPLC, excess DME is removed via vacuum distillation. The residue containing complexes of boron and arylethanolamine is subsequently cooled to 0°C. Quenching of the residue with 300 mL methanol gives the methylborate of arylethanolamine. The borate is then removed by azeotropic distillation as trimethylborate, leaving behind the desired arylethanolamine in the reaction mixture. An additional 300 ml of methanol and acetic acid (85 mL) are added to ensure the complete removal of trimethylborate via vacuum distillation to near dryness. The residue containing the boron-free arylethanolamine is cooled to 25°C and concentrated sulfuric acid (10.4 g, 0.221 mole) in water (64 mL) is added following by 570 ml of isopropyl alcohol. Albuterol sulfate is precipitated out as a white solid. After the reaction mixture is stirred at room temperature for 12 hrs and 0°C for 30 min the albuterol sulfate is filtered, washed with isopropyl alcohol (two 50 mL portions) and dried at 50°C for 12 hrs to give 49.75 g of the title compound (78% yield) as racemate.
The optically pure albuterol may be prepared by resolving a mixture of enantiomers methyl benzoate albuterol precursors which prepared by procedures well known to persons skilled in the art. The starting material 4- benzyl albuterol is commercially available from Cipla (Bombay, India).
(-)-D-Dibenzoyltartaric acid (D-DBTA) (32.2 g, 90 mmol, 1.0 eq) is added to a hot solution of racemic 4-benzyl albuterol (29.6 g, 90 mmol, 1.0 eq) in 180 mL of anhydrous denatured ethanol (type 3A, denatured with 5 vol % 2- propanol). The resulting solution is refluxed for 15 min and cooled to room temperature over 40 min and seeded with 99% ee (R)-4-benzyl albuterol DDBTA salt. The mixture is cooled to 5°-10°C and stirred for 1 hour. The white solid is collected by filtration and dried at 40°C and 28 inches of Hg for 1 hour to give (R)-4-benzyl albuterol D-DBTA salt (31.8 g, 50% yield, 83.6% ee). The solid is redissolved in 240 mL of ethanol at 55°-60°C and the solution is cooled to room temperature and stirred at room temperature for 2 hours and at 0°-5°C for 1 hour. The resulting solid is collected by filtration and dried at40°C and 28 inches of Hg for 2 hours as (R)-4-benzyl albuterol D-DBTA salt (22.9 g, 37.1% yield, 99.3% ee). The salt (22.9 g) is then treated with 204 mL of 5 wt % aq. Na2CO3 solution in 570 mL of ethyl acetate. The solid is worked-up, and recrystallization from 30 mL of ethyl acetate and 30 mL of nheptane gives optically pure (R)-4-benzyl albuterol free base as a white powder (10.1 g, 34.1% yield from racemic compound 99.6% ee and 99.8% purity).
A mixture of (R)-4-benzyl albuterol as a free base (3.2 g, 9.73 mmol) and 10% Pd/C (0.64 g) in 24 mL of ethanol (denatured with 5 vol % 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated to ca. 9 mL in volume containing crude (R)-albuterol and treated with anhydrous HCl in ether (1.0 M, 9.5 mL, 0.98 eq) at 0°-5°C. After 30 min at room temperature, 9 mL of methyl t-butyl ether (MTBE) is added, the resulting mixture is stirred at room temperature for 30 min and at 0°-5°C for 2 hours. The white solid (R)-albuterol hydrochloride is collected by filtration and recrystallized from 25 mL of ethanol and 12.5 mL of MTBE to give pure (R)-albuterol hydrochloride (2.17 g, 80.9% yield, 99.6% purity), white powder.
To a 3-neck flask immersed in an oil bath containing a solution of 40 g (0.206 mole) methyl 5-acetylsalicylate in 6 ml methylene chloride is charged with 82 ml of isopropanol. The solution is distilled to remove excess methylene chloride. When the internal temperature reaches 77°C, 126 ml (1.77 mole or 8.6 equivalents) of DMSO is added to the reaction mixture and the temperature of the mixture is increased to a temperature of 85° to 90°C. Then 33 ml (0.29 mole or 1.4 equivalents) of HBr (aqueous, 48%) is added to the mixture over a period of 20 minutes (exothermic), and the bath temperature is maintained at 95° to 100°C. As the addition of HBr nears completion distillation is initiated and dimethysulfide and isopropanol are distilled off. The mixture is stirred and the volume of the distillate monitored. After distillation of 82 ml of solvent, 20 ml of isopropanol is added slowly to maintain a steady rate of distillation. After the reaction completed asdetermined by high performance liquid chromatography (HPLC), the reaction mixture is quenched with 70 ml of 2.4 N H2SO4, the temperature of the reaction mixture is allowed to drop to 75°C and residual isopropanol is distilled off under vacuum. After a total of 165 ml distillate is collected, the title compound begins to precipitate. A mixture of 30 ml of acetonitrile and 70 ml of water is added slowly at 75°C with stirring. After 30 minutes of stirring, the reaction mixture is cooled to 15°C over a period of 90 minutes to complete the precipitation. The reaction mixture is filtered and the cake is washed with three 300 ml portions of water. The cake is dried in a draft oven at 50°C for 16 hours to give 39.5 g of the title compound (85% yield).
Preparation of albuterol from 5-glyoxyloyl-salicylic acid methyl ester
To a solution of 5-glyoxyloylsalicylic acid methyl ester hydrate (50 g, 0.221 mol) in ethylene glycol diethyl ether, 440 mL is added tertiary butylamine (16.2 g, 0.221 mol) at room temperature. The resulting light orange solution is stirred for 5 min until a clear solution is formed. The clear solution is then heated to reflux. Water and DME are distilled off azeotropically. After a total of 200 ml of distillate are collected, the solution is cooled to 25°C. The reaction mixture is slowly added to a solution containing 49 mL (0.49 mol) of 10.0 M borane-dimethyl sulfide in 220 mL of ethylene glycol diethyl ether (DME) at 70°C. The resulting reaction mixture is further refluxed for 2.5 hrs. After the reaction is completed as monitored by HPLC, excess DME is removed via vacuum distillation. The residue containing complexes of boron and arylethanolamine is subsequently cooled to 0°C. Quenching of the residue with 300 mL methanol gives the methylborate of arylethanolamine. The borate is then removed by azeotropic distillation as trimethylborate, leaving behind the desired arylethanolamine in the reaction mixture. An additional 300 ml of methanol and acetic acid (85 mL) are added to ensure the complete removal of trimethylborate via vacuum distillation to near dryness. The residue containing the boron-free arylethanolamine is cooled to 25°C and concentrated sulfuric acid (10.4 g, 0.221 mole) in water (64 mL) is added following by 570 ml of isopropyl alcohol. Albuterol sulfate is precipitated out as a white solid. After the reaction mixture is stirred at room temperature for 12 hrs and 0°C for 30 min the albuterol sulfate is filtered, washed with isopropyl alcohol (two 50 mL portions) and dried at 50°C for 12 hrs to give 49.75 g of the title compound (78% yield) as racemate.
The optically pure albuterol may be prepared by resolving a mixture of enantiomers methyl benzoate albuterol precursors which prepared by procedures well known to persons skilled in the art. The starting material 4- benzyl albuterol is commercially available from Cipla (Bombay, India).
(-)-D-Dibenzoyltartaric acid (D-DBTA) (32.2 g, 90 mmol, 1.0 eq) is added to a hot solution of racemic 4-benzyl albuterol (29.6 g, 90 mmol, 1.0 eq) in 180 mL of anhydrous denatured ethanol (type 3A, denatured with 5 vol % 2- propanol). The resulting solution is refluxed for 15 min and cooled to room temperature over 40 min and seeded with 99% ee (R)-4-benzyl albuterol DDBTA salt. The mixture is cooled to 5°-10°C and stirred for 1 hour. The white solid is collected by filtration and dried at 40°C and 28 inches of Hg for 1 hour to give (R)-4-benzyl albuterol D-DBTA salt (31.8 g, 50% yield, 83.6% ee). The solid is redissolved in 240 mL of ethanol at 55°-60°C and the solution is cooled to room temperature and stirred at room temperature for 2 hours and at 0°-5°C for 1 hour. The resulting solid is collected by filtration and dried at40°C and 28 inches of Hg for 2 hours as (R)-4-benzyl albuterol D-DBTA salt (22.9 g, 37.1% yield, 99.3% ee). The salt (22.9 g) is then treated with 204 mL of 5 wt % aq. Na2CO3 solution in 570 mL of ethyl acetate. The solid is worked-up, and recrystallization from 30 mL of ethyl acetate and 30 mL of nheptane gives optically pure (R)-4-benzyl albuterol free base as a white powder (10.1 g, 34.1% yield from racemic compound 99.6% ee and 99.8% purity).
A mixture of (R)-4-benzyl albuterol as a free base (3.2 g, 9.73 mmol) and 10% Pd/C (0.64 g) in 24 mL of ethanol (denatured with 5 vol % 2-propanol) is shaken on a Parr-hydrogenator under 50 psi of hydrogen at room temperature for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated to ca. 9 mL in volume containing crude (R)-albuterol and treated with anhydrous HCl in ether (1.0 M, 9.5 mL, 0.98 eq) at 0°-5°C. After 30 min at room temperature, 9 mL of methyl t-butyl ether (MTBE) is added, the resulting mixture is stirred at room temperature for 30 min and at 0°-5°C for 2 hours. The white solid (R)-albuterol hydrochloride is collected by filtration and recrystallized from 25 mL of ethanol and 12.5 mL of MTBE to give pure (R)-albuterol hydrochloride (2.17 g, 80.9% yield, 99.6% purity), white powder.
Brand name
Xopenex
Therapeutic Function
Bronchodilator
Clinical Use
Beta2
-adrenoceptor agonist:
Reversible airways disease
Reversible airways disease
Metabolism
Salbutamol is subject to first-pass metabolism in the
liver and possibly in the gut wall but does not appear to
be metabolised in the lung; the main metabolite is the
inactive sulphate conjugate.
Salbutamol is rapidly excreted, mainly in the urine, as metabolites and unchanged drug; a smaller proportion is excreted in the faeces.
Salbutamol is rapidly excreted, mainly in the urine, as metabolites and unchanged drug; a smaller proportion is excreted in the faeces.
Questions And Answer
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Description
Salbutamol is a bronchodilator medication that eases muscle tension in the airways adjoining with the lungs and enhances the flow of air circulating through the lungs. It is a short-acting medication that is used in the treatment of acute bronchopulmonary disorders which may include chronic obstructive pulmonary disorders (COPD), and chronic instances of bronchospasm resultant of acute bronchitis and bronchial asthma. It can also be used for the prophylactic treatment of training-induced bronchospasm. Salbutamol indicates 29 times more selectivity for beta2 receptors as compared to beta1 receptors, which gives it a higher specificity for adrenergic receptors positioned in the heart. Salbutamol comprises a racemic combination of Sand Risomers, where the R-isomer illustrates a higher affinity (about 150 times more) than the S-isomer, which is directly linked to increased toxicity. This has also influenced the development of levalbuterol. ; -
Indications
Salbutamol is indicated for the treatment of chronic asthma, maintenance of asthma, bronchitis, chronic obstructive pulmonary disease and uncomplicated preterm labor.
Salbutamol is an adrenergic bronchodilator, which is a class of medications that are inhaled through the mouth to ease tension in the bronchial tubes and the lungs. Such drugs also relieve shortness of breath, coughs, breathing complications, and wheezing by enhancing the circulation of air through the air passages. ; -
Contraindications
Salbutamol is contraindicated in patients who are hypersensitive to any of its formulation ingredients. The drug should not be prescribed for children under 4 years, pregnant women and elderly patients who are at high risk of developing kidney, liver and heart problems which are age-related. ; -
Dosage Information
For prevention or treatment of bronchospasm, children above 4 years and adults should inhale (aerosol & powder) 2 puffs every 4-6 hours as required. For prevention of training induced-bronchospasm, children above 4 years and adults should inhale (aerosol & powder) 2 puffs 15-30 minutes before the training session. For prevention and treatment of bronchospasm, children above 12 years and adults should take 2.5mg 3-4 times per day as a solution in a nebulizer, where children 2-12 years should take 0.63-1.25mg 3-4 times per day in a nebulizer. ; -
Pharmacodynamics
Salbutamol, which is a selective beta2-receptor inhibitor has a structure that resembles that of terbutaline, and it is widely indicated as a bronchodilator for the management of asthma and other acute obstructive airway infections. Levalbuterol, the R-isomer influences bronchodilation whereas the S-isomer enhances bronchial reactivity. Levalbuterol comprises the pure form of the R-enantiomer. Levalbuterol and Sepracor manufacturers maintain that the existence of the R-enantiomer results in less severe side effects. ; -
Mechanism of Action
Salbutamol is a beta2-adrenergic inhibitor hence it stimulates the beta2-adrenergic receptors. The bond between the drug and the beta2-receptors releases tension in the smooth muscles of the bronchi and the lungs. Salbutamol enhances the secretion of cyclic AMP by restoring adenylate cyclase, hence the drug-action is effectuated by cAMP. The stimulated cAMP enhances the functionality of cAMP-dependent Kinase A, and further suppresses the phosphorylation of myosin which reduces calcium levels within the cell. A reduction in calcium levels within the cell results in relaxation of the smooth muscles and bronchodilation. In addition, the drug suppresses the detachment of bronchorestricting agents from mast cells, suppresses microvascular leakage, and facilitates mucociliary clearance. ; -
Drug Interactions
Salbutamol may be prescribed alongside other medications depending on the condition of the patient and the effectiveness of the drug combination. However, Salbutamol may enhance the occurrence of certain side effects if it is combined with Trimipramine, Tianeptine, Opipramol, Protriptyline, Nortriptyline, Melitracen, Lofepramine, Levalbuterol, Imipramine, Doxepin, Dibenzepin, Desipramine, Clomipramine, Atomoxetine, Amoxapine, Amitriptylinoxide, Amitriptyline and Amineptine. This list is not all-inclusive hence one should also consult their doctor for dose adjustments. ; -
Route of Elimination
About 72% of inhaled Salbutamol is eliminated in urine 24 hours after inhalation, where 28% comprises the unaltered form of the drug and 44% as a metabolite. Salbutamol has a half-life of 1.6 hours. ; -
Precautions
Salbutamol should not be used in concurrent treatment with other inhaled medications such as terbutaline, pirbuterol, metaproterenol, levalbuterol and isoproterenol. The drug may result in paradoxical bronchospasm which may be life-threatening. ; -
Side Effects
Common side effects associated with salbutamol include shaking/trembling of the feet or hands, racing, irregular or fast pounding heartbeat. Less common side effects associated with the drug may include unusual weakness, chest tightness, swollen, painful or tender lymph nodes in the groin, neck or armpit, stomach pains, sore throat, runny nose, redness of the arms, neck, face and the upper chest, puffiness of the face, eyelids or the tongue, nausea, lower back pain, loss of appetite, hoarseness, skin rash, hives or itching, fever, diarrhoea, laboured breathing, difficulty in swallowing, coughs, chills, chest pains, bloody urine and bladder pain. In addition, more common side effects may also include congestion and voice changes. ;
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